As used in the art of peptide synthesis, the handle is defined as a bifunctional spacer that serves to link the peptide fragment or first amino acid to the polymer support. Many solid phase resins and handles are available in the art, as is described in Fields and Noble, 1990, Int. J. Pept. Protein Res. 35:161-214. To be useful, handles must be stable to the reaction conditions of peptide synthesis, but when the synthesis is complete, the handle needs to allow for cleavage of the peptide from the solid support.
A few handles that can be converted from a stable form of handle to a labile form have been designed and synthesized. Unfortunately, these handles have found no broad application in practice. For example, the 4-benzylthiophenyl- and 4-benzylsulfonyl-handle (D. L. Marshall, I. E. Liener: J. Org. Chem. 35, 867 (1970)) and sulfonamide-handle (G. W. Kenner, J. R. McDermott, R. C. Sheppard: Chem. Commun. 636, (1971)) have not found broad application. Further examples can be found in "The Peptides, Analysis, Synthesis, Biology," E. Gross, J. Meienhofer, Eds., Academic Press New York, vol. 2. p. 88 (1980), vol. 3. p. 209 (1981). Quite recently, the handle based on the 4-alkylthiobenzyl alcohol has been disclosed (EP 274,998 and EP 274,999; Chem. Abstr. 110, 135705 (1989)) and used in peptide synthesis. After reduction of the sulfoxide moiety, the 4-alkylthiobenzyl ester is cleaved to give a peptide with free carboxyl group.
The majority of aforementioned handles have, however, certain obvious limitations concerning the amino acid residues that can be affected by the conversion step. As a rule, oxidation steps cannot be used when the peptide contains sensitive amino acids such as tryptophan, cysteine, cystine, and methionine. Another problem is possible methylation during "activation" of handle and long cleavage times which can cause the damage of peptide.
Moreover, the handles presently available are not well adapted to both Boc and Fmoc synthetic procedures.